Abstract
Background
Maternal serum uric acid (UA) levels have been linked to adverse pregnancy outcomes, but no studies have yet examined this association in women undergoing assisted reproductive technology. This study aimed to investigate the relationship between pre-pregnancy UA levels and adverse pregnancy outcomes in women conceived via in vitro fertilization and embryo transfer (IVF-ET).
Methods
This retrospective cohort study included 2 111 singleton pregnancies conceived via IVF-ET, delivered at Peking University Third Hospital between 1 January 2017 and 30 April 2022. Restricted cubic splines were used to test nonlinear relationships between serum UA during pre-pregnancy and adverse outcomes, and multivariable logistic regression to calculate odds ratio (OR) and 95% confidence interval (CI).
Results
Of the 2 111 women, no significant associations were found between pre-pregnancy UA levels and preeclampsia, preterm birth, or macrosomia. However, a J-shaped relationship was observed for gestational diabetes mellitus (GDM) and low birth weight (LBW), and an inverse U-shaped relationship for gestational hypertension (GH). Reflecting these distinct non-linear topologies, statistically significant peak risks were observed and reported at different strata: women in the higher quintile (4th quintile) of UA had a 3.20-fold increased risk of GH (adjusted OR 3.20, 95% CI 1.23, 8.33) and a 1.38-fold increased risk of GDM (adjusted OR 1.38, 95% CI 1.01, 1.88) compared with the lowest quintile. Conversely, the risk of LBW accelerated sharply and peaked at the highest quintile (5th quintile) (adjusted OR 1.98, 95% CI 1.11, 3.54). In the subgroup analysis, the positive association between pre-pregnancy UA and LBW was more pronounced among patients with day 5 embryo transfer.
Conclusions
These findings suggest that optimizing serum UA levels in women planning pregnancy, particularly those undergoing IVF-ET, may have important clinical implications for improving pregnancy outcomes.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1186/s12978-026-02406-w.
Keywords: Uric Acid, Pre-pregnancy, Maternal outcomes, Neonatal outcomes, IVF-ET, Cohort Study
Introduction
Uric acid (UA) is the end metabolite synthesized in the liver through the oxidation of purine compounds, serving as an antioxidant, protecting cells from oxidative stress by scavenging free radicals [1, 2]. However, higher UA levels or hyperuricemia were associated with inflammation and endothelial dysfunction [3], contributing to the increased risk of numerous adverse pregnancy outcomes [4–6]. Hyperuricemia in the first trimester was linked to an increased risk of gestational diabetes mellitus (GDM) [7], and elevated serum UA in the second and third trimesters was associated with the onset of preterm delivery [8, 9]. Additionally, higher serum UA levels during pregnancy was associated with low birth weight (LBW) [10], small-for-gestational-age birth [11], and macrosomia [12]. Increasing evidence suggested that elevated serum UA levels were observed in preeclampsia and gestational hypertension (GH), and can be used as predictors of pregnancy complications [13, 14]. Previous studies predominantly focused on serum UA throughout pregnancy, but there was a notable paucity of data about effect of serum UA during pre-pregnancy on adverse pregnancy outcomes. Furthermore, majority of studies have identified linear relationships between serum UA levels and the risk of adverse pregnancy outcomes—suggesting that higher serum UA levels correspond to increased risks [15, 16], but one cohort study enrolling 3019 pregnant women in the United States [17] reported an inverse U-shaped relationship between serum UA levels and birth weight, indicating the complexity of serum UA’s role.
The use of in-vitro fertilization-embryo transfer (IVF-ET) has increased substantially worldwide over the past several decades [18], allowing infertile couples to conceive and have children. As of 2020, an estimated 8 million children had been conceived by assisted reproductive treatment (ART) around the world [19]. A national cross-sectional study using data of 1 211 303 cycles and 47 725 infants over 4 years in China, the number of infants born through IVF-ET accounted 1.69% of the total number of livebirths [20]. Most previous studies demonstrated that pregnancy by IVF-ET affected both short- and long-term outcomes for mothers and offspring, including hypertensive disorder of pregnancy, preeclampsia, GDM and preterm delivery [21–23]. However, the association between serum UA and pregnancy outcomes remains unclear among women conceived by IVF-ET.
In this retrospective cohort study, we aimed to examine the associations between serum UA during pre-pregnancy and pregnancy outcomes among women conceived by IVF-ET, and to explore whether the associations were modified by maternal key characteristics.
Methods
Study design and participants
This retrospective cohort study included pregnant women from the Reproductive Medical Center of the Peking University Third Hospital (Beijing, China). All pregnant women who conceived by IVF-ET were screened, and those gave livebirth between 1 January 2017 and 30 April 2022 were included in our study. The study was approved by the Research Ethics Commission of Peking University Third Hospital and the requirement for informed consent was waived by the Ethics Commission.
Exposure and covariates
The exposure of interest was serum UA during pre-pregnancy, measured using enzymatic colorimetric method. To minimize bias, the pre-pregnancy time window for UA level testing was defined as the baseline screening clinical visit within 3 months prior to the initiation of the controlled ovarian stimulation or controlled endometrial preparation cycle. The serum UA were then classified into quintiles, as highest, higher, middle, lower, and lowest quintiles (eTable 1 in Supplement).
Demographic, clinical, and laboratory data were extracted from inpatients’ electronic medical records, and all data were checked by two trained staff. Demographic information included maternal age and, pre-pregnancy body mass index (BMI), and additional information regarding prior diagnoses of diabetes mellitus, chronic hypertension, polycystic ovarian morphology, and obstetric history such as number of gestations and parity was collected. Clinical information included in vitro fertilization (IVF), therapy regimen, embryo type, and cycle type, method of delivery. Laboratory information comprised measurements of blood glucose, systolic blood pressure, diastolic blood pressure, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2).
Outcomes
Maternal outcomes were eclampsia or preeclampsia, GH, and GDM. Preeclampsia was defined as new-onset blood pressures ≥ 140/90 mmHg after 20 weeks of gestation and combined with albuminuria ≥ 0.3 g. GH was defined as a systolic blood pressure of ≥ 140 mmHg or a diastolic blood pressure of ≥ 90 mmHg, on two occasions at least 4 h apart after 20 weeks of gestation without proteinuria or severe features. GDM is defined as fasting plasma glucose ≥ 5.1 mmol/L, 1-h plasma glucose ≥ 10.0 mmol/L, or 2-h plasma glucose ≥ 8.5 mmol/L on an oral glucose tolerance test, occurring or first diagnosed during pregnancy. Neonatal outcomes were preterm birth, LBW, and macrosomia. Preterm delivery was defined as a live birth delivered before 37 weeks of pregnancy. LBW was defined as birth weight < 2500 g. Macrosomia was defined as birth weight > 4000 g.
Statistical analysis
Descriptive analysis of demographic, clinical, and laboratory characteristics was performed, with mean ± standard deviation (SD) for continuous variables and frequency with percentage (%) for categorical variables. The characteristics across pre-pregnancy serum UA groups were compared using Chi-square tests and one-way analysis of variance, as appropriate.
Restricted cubic splines with 5 knots at 5%, 27.5%, 50%, 72.5%, and 95% were used to assess the linear or nonlinear relationships of serum UA with probability of adverse outcomes. Ordinary differential equations were then used to solve for the second-order derivatives (risks of adverse pregnancy outcomes/serum UA) to determine the inflection point.
Univariate and multivariable logistic regression models were constructed to examine whether the low or high quintile of serum UA was associated with adverse pregnancy outcomes, and the results were expressed using odds ratios (ORs) and 95% confidence intervals (CIs). In multivariable analysis, the adjusted covariates included chronic hypertension, diabetes, polycystic ovarian morphology, indications of IVF, regimen of therapy, embryo type, cycle type, method of delivery, number of gestation, parity, pre-pregnancy BMI, systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride, HDL, LDL, FSH, LH, and E2.
Sensitivity analysis was conducted by restricting the study population to women without diagnosed diabetes before pregnancy (n = 2041) to assess the robustness of the findings. The stratified analyses were performed to examine the associations according to polycystic ovarian morphology, embryo type, and cycle type, and the significant difference in stratified models were further evaluated by adding a multiplicative interaction term into multivariable models.
All data were analyses using SAS software, version 9.4 (SAS Institute, Inc). Statistical significance was defined as a two-sided P < 0.05.
Results
In total, 118,279 women underwent IVF-ET in Peking University Third Hospital between 1 January 2017 and 30 April 2022. Among them, 3047 pregnant women delivered live births and were originally included in the study. After excluding 936 pregnant women with twin pregnancies, we included 2111 singleton pregnant women in the final analysis (eFigure 1 in Supplement).
The average age of the 2111 pregnant women was 34.8 years (SD 3.6), ranging from 23 to 46 years, with the majority being nulliparous (Table 1 and eTable 2 in Supplement). Demographic, clinical, and laboratory characteristics varied significantly across quintile of pre-pregnancy serum UA. For clarity in reporting these associations, the fourth and fifth serum UA quintiles are hereinafter referred to as the 'higher' and 'highest' quintiles, respectively. The prevalence of overweight and obesity was higher in the highest serum UA quintile compared to the lowest quintile. Comorbidities including chronic hypertension and diabetes were more likely to present in the highest serum UA quintile. Women in the highest quintile also showed a higher prevalence of polycystic ovarian morphology and were more likely to have undergone recovery cycles and to undergo embryo transfer following IVF-ET based on day 5 after oocyte retrieval. The mean total cholesterol, triglyceride, and LDL were higher in the highest serum UA quintile than the lowest quintile.
Table 1.
Characteristics according to quintiles of serum uric acid during pre-pregnancya
| Serum uric acid (μmol/L) | ||||||
|---|---|---|---|---|---|---|
|
Total (N = 2111) |
Lowest (n = 418) |
Lower (n = 414) |
Middle (n = 421) |
Higher (n = 434) |
Highest (n = 424) |
|
| Maternal age, mean (SD), y | 34.8 ± 3.6 | 34.8 ± 3.4 | 34.8 ± 3.5 | 34.9 ± 3.8 | 34.5 ± 3.6 | 34.8 ± 3.6 |
| Chronic hypertension | ||||||
| No | 2029 (96.1) | 413 (98.8) | 408 (98.6) | 409 (97.1) | 407 (93.8) | 392 (92.5) |
| Yes | 82 (3.9) | 5 (1.2) | 6 (1.4) | 12 (2.9) | 27 (6.2) | 32 (7.5) |
| Diabetes | ||||||
| No | 2041 (96.7) | 411 (98.3) | 406 (98.1) | 405 (96.2) | 417 (96.1) | 402 (94.8) |
| Yes | 70 (3.2) | 7 (1.7) | 8 (1.9) | 16 (3.8) | 17 (3.9) | 22 (5.2) |
| Pre-pregnancy body mass index | 22.2 ± 3.2 | 21.2 ± 2.6 | 21.6 ± 2.9 | 22.0 ± 2.8 | 22.6 ± 3.3 | 23.8 ± 3.5 |
| Underweight | 157 (7.4) | 47 (11.2) | 42 (10.1) | 28 (6.7) | 24 (5.5) | 16 (3.8) |
| Normal weight | 1237 (58.6) | 281 (67.2) | 268 (64.7) | 262 (62.2) | 242 (55.8) | 184 (43.4) |
| Overweight | 560 (26.5) | 79 (18.9) | 85 (20.5) | 112 (26.6) | 130 (30.0) | 154 (36.3) |
| Obesity | 157 (7.4) | 11 (2.6) | 19 (4.6) | 19 (4.5) | 38 (8.8) | 70 (16.5) |
| Polycystic ovarian morphology | ||||||
| No | 1859 (88.1) | 383 (91.6) | 365 (88.2) | 385 (91.4) | 377 (86.9) | 349 (82.3) |
| Yes | 252 (11.9) | 35 (8.4) | 49 (11.8) | 36 (8.6) | 57 (13.1) | 75 (17.7) |
| Number of gestation | ||||||
| 0 | 1318 (62.4) | 273 (65.3) | 264 (63.8) | 257 (61.1) | 271 (62.4) | 253 (59.7) |
| 1 | 473 (22.4) | 92 (22.0) | 86 (20.8) | 93 (22.1) | 90 (20.7) | 112 (26.4) |
| 2 | 204 (9.7) | 28 (6.7) | 39 (9.4) | 49 (11.6) | 47 (10.8) | 41 (9.7) |
| ≥ 3 | 116 (5.5) | 25 (6.0) | 25 (20.0) | 22 (5.2) | 26 (6.0) | 18 (4.2) |
| Parity | ||||||
| Multiparity | 106 (5.0) | 18 (4.3) | 22 (5.3) | 16 (3.8) | 32 (7.4) | 18 (4.2) |
| Nulliparity | 2005 (95.0) | 400 (95.7) | 392 (94.7) | 405 (96.2) | 402 (92.6) | 406 (95.8) |
| Embryo type | ||||||
| D3 | 1194 (56.6) | 274 (65.6) | 254 (61.4) | 230 (54.6) | 226 (52.1) | 210 (49.5) |
| D5 | 917 (43.4) | 144 (34.4) | 160 (38.6) | 191 (45.4) | 208 (47.9) | 214 (50.5) |
aUnless indicated otherwise, values are presented as number (percentage) of deliveries
Percentages may not sum to 100 due to rounding
The prevalence of most outcomes, with the exception of macrosomia, increased across quintile of pre-pregnancy serum UA, and was highest among those in the higher or highest quintiles (Table 2). For instance, the prevalence of eclampsia or preeclampsia was 4.78%, 6.76%, 5.94%, 9.22%, and 12.03% from the lowest to highest quintiles, respectively (P for trend < 0.001).
Table 2.
Pregnancy outcomes across quintiles of serum uric acid during pre-pregnancya
| Serum uric acid (μmol/L) | |||||||
|---|---|---|---|---|---|---|---|
|
Total (N = 2111) |
Lowest (n = 418) |
Lower (n = 414) |
Middle (n = 421) |
Higher (n = 434) |
Highest (n = 424) |
P for trend | |
| Eclampsia or preeclampsia | 164 (7.77) | 20 (4.78) | 28 (6.76) | 25 (5.94) | 40 (9.22) | 51 (12.03) | 0.001 |
| Gestational hypertension | 78 (3.69) | 6 (1.44) | 11 (2.66) | 19 (4.51) | 22 (5.07) | 20 (4.72) | 0.021 |
| Gestational diabetes mellitus | 704 (33.35) | 118 (28.23) | 134 (32.37) | 127 (30.17) | 161 (37.10) | 164 (38.68) | 0.004 |
| Preterm birth | 217 (10.28) | 34 (8.13) | 34 (8.21) | 38 (9.03) | 48 (11.06) | 63 (14.86) | 0.006 |
| Low birthweight | 150 (7.11) | 22 (5.26) | 25 (6.04) | 24 (5.70) | 34 (7.83) | 45 (10.61) | 0.015 |
| Macrosomia | 139 (6.58) | 24 (5.74) | 21 (5.07) | 24 (5.70) | 31 (7.14) | 39 (9.20) | 0.112 |
aValues are presented as number (percentage) of deliveries
When pre-pregnancy serum UA was analyzed as a continuous variable (in 1 μmol/L increments), higher serum UA was associated with increased risks of several adverse outcomes in women who conceived via IVF-ET (Fig. 1), even after adjusting for maternal demographic, clinical, and laboratory characteristics. The relationships between serum UA and the ORs for adverse outcomes showed distinct pattern with reverse-U-shaped or J-shaped relationships (nonlinear P for trend < 0.001). The ORs for GH increased sharply as serum UA levels approached 300 μmol/L and then decreased, while the ORs for GDM and LBW increased steadily as serum UA approached 330 μmol/L and 335 μmol/L, respectively, and then accelerated rapidly.
Fig. 1.
The relationships between serum uric acid during pre-pregnancy and adverse pregnancy outcomes. The odds ratios of adverse pregnancy outcomes were estimated by logistic regression model with restricted cubic splines, adjusting for chronic hypertension, diabetes, polycystic ovarian morphology, indications of IVF, regimen of therapy, embryo type, cycle type, method of delivery, number of gestation, parity, pre-pregnancy BMI, systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride, HDL, LDL, FSH, LH, and E2. The solid line represents the odds ratios of adverse pregnancy outcomes, and the dashed line represents the 95% Cis
Without adjusting for the confounders, the highest quintile of pre-pregnancy serum UA was associated with increased risk of eclampsia or preeclampsia (OR 2.72, 95% CI 1.59–4.68), GDM (OR 1.60, 95% CI 1.20–2.14), preterm birth (OR 2.11, 95% CI 1.34–3.30), and LBW (OR 2.14, 95% CI 1.26–3.63), and higher quintile was associated with increased risk of GH (OR 3.67, 95% CI 1.47–9.14), compared with the lowest quintile (Table 3). After adjustment for maternal characteristics, the magnitude of the associations for eclampsia or preeclampsia and preterm birth decreased, and became non-significant; and associations for GH, GDM, and LBW were attenuated but remained positive (Table 3). For example, the ORs of the association between the highest quintile of pre-pregnancy serum UA and risk of GDM was 42% higher than lowest quintile with adjustment for confounders. The associations did not substantially change when the analysis was restricted to women with no diagnosed diabetes during pre-pregnancy (eTable 3 in Supplement). In addition, a significant multiplicative interaction between embryo type and quintile of pre-pregnancy serum UA was observed for the risk of LBW (P-interaction = 0.015). The association between higher serum uric acid and increased risk of low birth weight appeared to be more pronounced among women undergoing day 5 embryo transfer compared with day 3 embryo transfer after oocyte retrieval. (eTable 4 in Supplement).
Table 3.
Associations between quintiles of serum uric acid during pre-pregnancy and pregnancy outcomesa
| Serum uric acid (μmol/L) | ||||||
|---|---|---|---|---|---|---|
| Lowest | Lower | Middle | Higher | Highest | P for trend | |
| Eclampsia or preeclampsia | ||||||
| Unadjusted | Reference | 1.44 (0.80–2.61) | 1.26 (0.69–2.30) | 2.02 (1.16–3.52) | 2.72 (1.59–4.65) | < 0.001 |
| Adjusted | Reference | 1.44 (0.78–2.68) | 0.98 (0.52–1.85) | 1.38 (0.76–2.52) | 1.41 (0.77–2.59) | 0.897 |
| Gestational hypertension | ||||||
| Unadjusted | Reference | 1.87 (0.69–5.12) | 3.25 (1.28–8.21) | 3.67 (1.47–9.14) | 3.40 (1.35–8.55) | 0.002 |
| Adjusted | Reference | 1.83 (0.65–5.12) | 2.86 (1.10–7.49) | 3.20 (1.23–8.33) | 1.94 (0.71–5.29) | 0.884 |
| Gestational diabetes mellitus | ||||||
| Unadjusted | Reference | 1.22 (0.91–1.64) | 1.10 (0.82–1.48) | 1.50 (1.12–2.00) | 1.60 (1.20–2.14) | < 0.001 |
| Adjusted | Reference | 1.21 (0.89–1.65) | 1.03 (0.75–1.41) | 1.38 (1.01–1.88) | 1.42 (1.03–1.97) | 0.023 |
| Preterm birth | ||||||
| Unadjusted | Reference | 1.05 (0.63–1.73) | 1.16 (0.71–1.90) | 1.47 (0.92–2.35) | 2.11 (1.34–3.30) | < 0.001 |
| Adjusted | Reference | 0.98 (0.58–1.64) | 1.00 (0.60–1.67) | 1.14 (0.70–1.88) | 1.53 (0.94–2.50) | 0.057 |
| Low birthweight | ||||||
| Unadjusted | Reference | 1.16 (0.64–2.09) | 1.09 (0.60–1.97) | 1.53 (0.88–2.66) | 2.14 (1.26–3.63) | 0.002 |
| Adjusted | Reference | 1.21 (0.66–2.22) | 1.10 (0.60–2.03) | 1.46 (0.82–2.60) | 1.98 (1.11–3.54) | 0.016 |
| Macrosomia | ||||||
| Unadjusted | Reference | 0.88 (0.48–1.60) | 0.99 (0.55–1.78) | 1.26 (0.73–2.19) | 1.66 (0.98–2.82) | 0.019 |
| Adjusted | Reference | 0.89 (0.48–1.64) | 0.93 (0.51–1.69) | 1.21 (0.68–2.15) | 1.65 (0.93–2.92) | 0.044 |
aUnless indicated otherwise, values are presented as odds ratios (95% CIs)
Adjustment for chronic hypertension, diabetes, polycystic ovarian morphology, indications of IVF, regimen of therapy, embryo type, cycle type, method of delivery, number of gestation, parity, pre-pregnancy BMI, systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride, high density lipoprotein cholesterol, low-density lipoprotein cholesterol, FSH, LH, and E2
Discussion
This cohort study of 2111 singleton pregnant women who conceived by IVF-ET, to our knowledge, is the first to investigate the relationship between serum UA during pre-pregnancy and pregnancy outcomes. We found that serum UA during pre-pregnancy was associated with GH, GDM and LBW, independent from maternal age, BMI and other confounders. A critical finding was that there is a J-shaped association of pre-pregnancy serum UA with GDM and LBW, and an inverse U-shaped association of pre-pregnancy serum UA with GH.
Increasing evidence suggested a positive relationship between high serum UA and high systolic/diastolic blood pressure, implicating serum UA in the progression of HDP [24–26]. A multicenter cohort study of 3019 pregnant women indicated that diastolic blood pressure and mean arterial pressure showed a J-shaped relationship with maternal UA [27]. In addition, a cohort study including 4725 singleton pregnant women found that first trimester serum UA levels over 240 mmol/L was associated with a 25% increased risk of preeclampsia [28]. Our findings showed that compared with the women in the lowest quintile of pre-pregnancy serum UA, those in the highest quintile had a threefold increased risk of GH, whereas no increased risk was found for eclampsia or preeclampsia.
Previous studies have identified serum UA as a predictive factor for GDM, with early pregnancy being the optimal time for testing [29]. A cohort study of 23 843 singleton pregnant women found that compared to serum UA below 240 mmol/L, the risks of GDM increased by 29%–56% for serum UA between 240 and 300 mmol/L, and by 55%–115% for serum UA above 300 mmol/L [30]. Additionally, a retrospective analysis of 18 250 mother-infant pairs in a large obstetric center in China suggested that hyperuricemia during early pregnancy increased the risks of GDM by 39% [15]. While there was no evidence on the association between pre-pregnancy serum UA and GDM, our study suggested that pre-pregnancy serum UA was an independent risk factor of GDM among women conceived by IVF-ET. Compared with the lowest quintile of pre-pregnancy serum UA, the highest quintile had a 42% higher risk of GDM.
Studies have found that higher serum UA levels during pregnancy were associated with increased risks of neonatal adverse outcomes, including preterm birth [6], LBW [10], small-for-gestational-age birth [11], and macrosomia [12]. However, in our study, pre-pregnancy serum UA were only associated with an elevated risk of LBW, with the risks of LBW increasing by 98% in the highest serum UA quintile as compared with the lowest serum UA quintile. Additionally, previous studies have demonstrated that Day 5/6 embryo transfer yields higher pregnancy rates compared to Day 3 ET, without affecting maternal and neonatal outcomes [31, 32]. While our study revealed an interaction between serum UA levels and the timing of ET concerning birth weight. This finding warrants further investigation to confirm the association and elucidate the underlying mechanisms.
Possible mechanisms underlying the relationship of pre-pregnancy serum UA with adverse pregnancy outcomes are multifaceted. High serum UA has been associated with endothelial dysfunction and reduced nitric oxide bioavailability, which may contribute to impaired vascular reactivity and altered metabolic homeostasis [33]. Additionally, higher uric acid levels have been linked to systemic inflammatory activation and oxidative stress, which are recognized contributors to metabolic dysregulation and insulin resistance [34]. Regarding GH and PE, uric acid has been reported to correlate with vascular dysfunction and increased arterial stiffness, which may reflect underlying vascular susceptibility rather than a direct causal pathway [35, 36]. For neonates, high serum UA levels has been associated with oxidative stress and placental dysfunction, which may potentially affect nutrient transport and fetal growth [37, 38]. Notably, serum UA may also cross the maternal–fetal interface, influencing neonatal outcomes and explaining our finding that high serum UA was associated with LBW [17].
Our study found a J-shaped relationship between pre-pregnancy serum UA and the risks of GDM and LBW, and an inverted U-shaped relationship for GH. This inverted U-shaped topology inherently explains the apparent contradiction in Table 3, where a highly significant risk was observed in the higher quintile (adjusted OR 3.20, 95% CI 1.23–8.33) while the overall adjusted trend test was non-significant (P for trend = 0.884). Because the standard trend test specifically evaluates a unidirectional, monotonic linear relationship, its statistical power is neutralized when the risk curve peaks at the higher quintile and subsequently declines or flattens at the highest quintile. The observed decrease in GH risk at extremely high UA levels lacks clear mechanistic explanation and may be due to the insufficient sample size of women with exceptionally high UA. Other possible reasons could include potential compensatory mechanisms at very high UA levels, or unmeasured confounding factors that may influence this association. Further research is needed to elucidate these findings.
This study has several limitations. First, it was conducted at a large medical center, a public referral hospital, where women are more likely to have complicated pregnancies, potentially leading to admission rate bias and an overestimation of the effects of pre-pregnancy serum UA on adverse pregnancy outcomes. Second, due to the retrospective design, serum UA levels were not recorded at a specific and unified time point, introducing variability and potential bias among individuals. Third, glycosylated hemoglobin levels were not recorded, as it is not typically measured during pre-conception testing, which could bias the analysis of the connection between serum UA and GDM. Finally, unmeasured maternal disease history and socioeconomic factors may have introduced additional bias into the analysis.
Conclusions
This study found that high serum UA during pre-pregnancy was independently associated with increased risks of GH, GDM, and LBW, and the risk of LBW was more pronounced in women undergoing embryo transfer following IVF-ET based on day 5 after oocyte retrieval but not on day 3. A J-shaped relationship of serum UA with the risks of GDM and LBW, as well as an inverse U-shaped relationship with GH, were observed, with inflection points around 300–335 μmol/L. These findings suggest that monitoring and managing serum UA levels in women planning pregnancy, especially those undergoing IVF-ET, could have significant clinical implications for improving maternal and neonatal outcomes.
Supplementary Information
Acknowledgements
Not applicable.
Abbreviations
- UA
Uric Acid
- IVF-ET
In-Vitro Fertilization-Embryo Transfer
- GH
Gestational Hypertension
- GDM
Gestational Diabetes Mellitus
- LBW
Low Birth Weight
Authors’ contributions
KL and SY analyzed and interpreted the patient data regarding pre-pregnancy uric acid and pregnancy outcomes. YWang, RL, YZ, and YWei were responsible for data collection and clinical coordination. SC and ZL designed the study, supervised the project, and were major contributors in writing and revising the manuscript. All authors read and approved the final manuscript.
Funding
This work was supported by the Outstanding returnees research start-up fund of Peking University Third Hospital (BYSYLXHG2020005), the Key clinical projects of the Peking University Third Hospital (BYSYZD2021014), and the Opening fund of NHC Key Laboratory of Reproductive Health.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki. The study was approved by the Reproductive Medicine Ethics Committee of Peking University Third Hospital (Project number: 2018sz-002). The requirement for informed consent was waived by the Ethics Commission due to the retrospective nature of the study.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Shaomin Chen, Email: chenshaomin1999@163.com.
Zhaoping Li, Email: zhaoping1223@163.com.
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Data Availability Statement
No datasets were generated or analysed during the current study.